Topical NSAIDS and related solutes are often applied to the skin to target tissues directly below the application site. We have used both biopsy and microdialysis techniques to show that most solutes penetrate below dermal capillaries into the subcutaneous and deeper tissues of both rats and human subjects. The selectivity of local penetration is time related, the concentrations in underlying tissues at longer times often being defined by recirculation from the systemic blood supply. Increased depths of penetration may be achieved by the use of vasoactive agents. Iontophoretic and other delivery systems appear to increase the efficiency of drug delivery through the stratum corneum and do not appear to greatly facilitate penetration into tissues below the dermis. Vehicle polarity and solute properties such as size can be used to advantage in delivering NSAIDs to deeper tissues.The pharmacokinetics of NSAIDs in the dermis and other tissues appears to be related to the absorption of solutes through the stratum corneum, binding of the NSAIDs to dermal and other tissues and clearance of NSAIDs from these tissues through either diffusion into deeper tissues or removal by the systemic blood supply. The latter is dependent on the blood flow to the tissues and protein binding of the NSAIDs in the blood. Absorption of NSAIDs and other solutes through the stratum corneum is defined by their inherent hydrogen bonding ability, lipophilicity and size as well as the interactions between the solute, vehicle and skin.The literature contains a number of examples of pharmacological efficacy after topical application which can now be better explained in terms of our recently gained understanding of the pharmacokinetics of NSAIDs after topical application. A complicating aspect in this interpretation is the variation in efficacy between the various models used to date.